The protective outer layers of the skin known as the epidermis belong to a group of tissues in the body that are turning over at a rapid rate. The majority of epidermal cells have a lifespan of just 2-3 weeks, and are shed as mature cells from the skin's surface. These cells are replaced by continuous cell regeneration in the innermost basal layer, which contains the potent epidermal stem cells. In addition, epidermal stem cells are thought to play a central role in repairing damaged tissue and their unique ability for self-renewal and extended proliferation makes them a highly desirable target for tissue and organ regeneration as well as transplantation and gene therapy. Studies to date suggest that the tissue regenerative ability of epidermal progenitors is regulated by cellular interactions between the epidermis and the adjacent connective tissue i.e. the dermis which is a complex and heterogeneous tissue. Given that the precise nature of specific molecular signals provided by the dermis are poorly understood, the aims of this project are to define the role of two microenvironmental elements that appear to have a role in promoting epidermal tissue regeneration :(i) the basement membrane proteins laminin-10/11; and (ii) a specific subset of dermal cells that reside adjacent to the epidermal stem cells. In addition to investigating the role of known growth factors secreted by the dermis, we plan to identify further genes with a role in promoting epithelial tissue regeneration. These studies may provide improved conditions for the ex-vivo expansion of epidermal cells for therapeutic applications and be beneficial for the treatment of severe burns patients who have to be hospitalised for prolonged periods while sufficient numbers of their skin cells are grown up for transplantation. The proposed studies may also provide a means for expanding all keratinocyte progenitors by manipulation of growth factors and extracellular matrix proteins.